The proposed project is aimed at developing a new and general method for improved delivery of various drugs through the blood-brain barrier, as well as, to achieve brain specific drug delivery by affecting the bidirectional movement of the drugs in and out of the brain. The proposed method is based on the bioreversible dihydropyridine yields reversibly pyridinium salt type redox system, which was already successfully used by us for delivery to the brain of a quaternary pyridinium type drug, N-methylpyridinium-2-carbaldoxime chloride (2-PAM). It is suggested that analogous dihydropyridine yields reversibly pyridinium type systems can be used as carriers to the brain for numerous drugs, such as antitumor agents, steroid hormones, CNS drugs, which as dihydropyridine carrier derivatives would penetrate the blood-brain barrier. Upon oxidation to the corresponding pyridinum salts, the elimination of these derivatives would be hindered, resulting in higher relative concentrations in the brain. Upon cleavage of the carrier part, the active drugs will be released in the brain in a controllable manner, while the carrier parts (selected to be nontoxic) will be eliminated from the brain, as indicated by our recent studies. It is proposed first to study simple carrier systems of this type, such as N-alkyl nicotinic acid esters and amides, N-alkyl pyridinium aldoxime ethers and esters, in order to establish their relative availability and stability. Basic synthetic and chemical kinetic studies of these redox systems will be carried out first, including the investigation of the stabilizing and destabilizing effects of various substituents. Selected systems will then be studied in vivo for delivery characteristics (bidirectional kinetics through the blood-brain barrier) to the brain, using radiolabeled compounds. The best carrier groups will then be used for delivery of selected target drugs. Certain quaternary pyridinium type drugs will also be studied for their improved direct brain delivery by transforming them into the corresponding dihydro-derivatives. Significant improvement in the therapeutic index of drugs necessary to be delivered to the brain.